2-aminoalkylaminoquinolines as dopamine D4 ligands

ABSTRACT

Disclosed are compounds of the formula                    
     or the pharmaceutically acceptable salts thereof wherein: 
     A represents an optionally substituted alkylene group of from 2-5 carbon atoms; 
     W is COH or CH; 
     Y and Z are nitrogen or CH; and 
     R 1 , R 2 , R 3 , R 4 , R 5 , R 6  are defined herein. 
     Pharmaceutical compositions and preparations containing such compounds are also provided. The invention further relates to the use of such compounds in the treatment of neuropsychological diseases such as schizophrenia and other central nervous system diseases.

This application is a 371 of PCT/US98/14235, filed Jun. 11, 1998, whichclaims priority from U.S. Provisional Application Ser. No. 60/049,517,filed Jun. 13, 1997.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to aminoquinoline derivatives which selectivelybind to brain dopamine receptor subtypes. More specifically, it relatesto 2-quinolyl(azacycloalkylalkyl)amines and pharmaceutical compositionsand preparations containing such compounds. It also relates to the useof such compounds in the treatment or prevention ofneuropsychochological disorders such as schizophrenia and other centralnervous system diseases.

2. Description of the Related Art

The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the brain. The dopamine D₄ receptor subtype has recently beenidentified. See Nature 350: 610 (Van Tol et al., 1991) and Nature, 347:146 (Sokoloff et al., 1990). Its unique localization in limbic brainareas and its differential recognition of various antipsychotics suggestthat the D₄ receptor plays a role in the etiology of schizophrenia.Consequently, selective D₄ antagonists are considered effectiveantipsychotics free from the neurological side effects displayed byconventional neuroleptics.

U.S. Pat. No. 5,093,333 describes N-substituted-2-aminoquinolines saidto be M₁ receptor agonists.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdopamine receptor subtypes. A broad aspect of the invention is directedto compounds of Formula I:

wherein:

R₁, R₂, and R₃ independently represent hydrogen, halogen, C₁-C₆ alkyl,C₁-C₄ alkoxy, C₁-C₄ alkylthio, hydroxy, amino, mono(C₁-C₆) alkylamino,di(C₁-C₆) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy;

R₆ is hydrogen or C₁-C₆ alkyl; and

Q represents a substituted azacycloalkylalkyl group of the formula:

 where

W is nitrogen, CH or COH;

A represents an alkylene group of from 2-5 carbon atoms optionallysubstituted with one or more alkyl groups having from one to four carbonatoms; and

T is an aryl or heteroaryl moiety optionally substituted with up to twogroups selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, hydroxy, amino, mono(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,cyano, nitro, trifluoromethyl and trifluoromethoxy.

In yet another aspect, the invention provides pharmaceuticalcompositions comprising compounds of Formula I.

Since dopamine D₄ receptors are concentrated in the limbic system(Taubes, Science 265: 1034, 1994) which controls cognition and emotion,compounds which interact with these receptors are useful in thetreatment of cognitive disorders. Such disorders include cognitivedeficits which are a significant component of the negative symptoms(social withdrawal and unresponsiveness) of schizophrenia. In addition,disorders involving memory impairment or attention deficit disorders canbe treated with the compounds of this invention. These compoundsinteract specifically with the dopamine D₄ receptor subtype.

The compounds of the invention demonstrate high affinity and selectivityin binding to the D₄ receptor subtype. The use of the compounds of thisinvention in methods of treating neuropsychological disorders ispredicated on the ability of the compounds to bind selectively to adopamine receptor subtype, the D₄ receptor. The compounds of theinvention can therefore be used in the treatment of schizophrenia,psychotic depression and mania. Other dopamine-mediated diseases such asParkinsonism and tardive dyskinesias can also be treated directly orindirectly by modulation of D₄ receptors.

Thus, in another aspect, the invention provides methods for treatingand/or preventing neuropsychological disorders including, for example,schizophrenia, mania, dementia, depression, anxiety, compulsivebehavior, substance abuse, memory impairment, cognitive deficits,Parkinson-like motor disorders and motion disorders related to the useof neuroleptic agents. It also provides methods of treating affectivedisorders such as Alzheimer's disease and certain movement disorderssuch as Parkinsonism and dystonia.

The invention further provides methods for treating the extrapyramidalside effects associated with the use of conventional neuroleptic agents.The compounds of the present invention are also useful for the treatmentof other disorders which respond to dopaminergic blockade such assubstance abuse and obsessive compulsive disorder.

DETAILED DESCRIPTION OF THE INVENTION

In addition to the compounds of Formula I above, the inventionencompasses compounds of Formula IA:

wherein:

R₁, R₂, R₃, R₄ and R₅ are the same or different and represent hydrogen,halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, hydroxy, amino,mono(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, cyano, nitro,trifluoromethyl or trifluoromethoxy;

R₆ is hydrogen or C₁-C₆ alkyl;

W is nitrogen, COH, or CH;

Y and Z independently represent nitrogen or CH; and

A represents an alkylene group of from 2-5 carbon atoms optionallysubstituted with one or more alkyl groups having from one to four carbonatoms.

In Formula IA, the dashed segment represents either a single bondresulting in a 3,4 dihydroquinoline; or a double bond resulting in aquinoline.

In the compounds of the invention, “W” preferably represents nitrogen orCOH. Preferred “T” groups in Formula I are 6-membered carbocyclicaromatic ring systems having zero, one or two nitrogen atoms.Particularly preferred “T” groups are phenyl, 2-pyridinyl, and2-pyrimidinyl. The particularly preferred “T” groups are optionallymono- or disubstituted with halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄alkylthio, hydroxy, amino, mono(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino,cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of Formula IA are those where R₆ is hydrogen, methylor ethyl.

Preferred “T” groups in Formula I are

The invention also provides compounds of Formula II:

wherein:

R₁, R₂, R₃, R₄ and R₅ are the same or different and represent hydrogen,halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, hydroxy, amino,mono(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, cyano, nitro,trifluoromethyl or trifluoromethoxy;

R₆ is hydrogen or C₁-C₆ alkyl;

W is nitrogen, COH, or CH;

Y and Z independently represent nitrogen or CH; and

A represents an alkylene group of from 2-5 carbon atoms optionallysubstituted with one or more alkyl groups having from one to four carbonatoms.

Preferred compounds of Formula II are those where R₆ is hydrogen, methylor ethyl. Particularly preferred compounds of Formula II are those where

In addition, the invention encompasses compounds of Formula III:

wherein:

R₁, R₂, R₃, R₄ and R₅ are the same or different and represent hydrogen,halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, hydroxy, amino,mono(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, cyano, nitro,trifluoromethyl or trifluoromethoxy;

R₆ is hydrogen or C₁-C₆ alkyl;

W is nitrogen, COH, or CH;

Y and Z independently represent nitrogen or CH; and

A represents an alkylene group of from 2-5 carbon atoms optionallysubstituted with one or more alkyl groups having from one to four carbonatoms.

In preferred compounds of Formula III, R₆ is hydrogen, methyl or ethyl.

In certain situations, compounds of Formula I may contain one or moreasymmetric carbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates oroptically active forms. For example, where R₆ in Formula I is a methylgroup, the resulting compound can be present as (R) and (S)stereoisomers. In these situations, the single enantiomers, i.e.,optically active forms, can be obtained by asymmetric synthesis or byresolution of the racemates. Resolution of the racemates can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable salts. If the compound of theinvention is obtained as an acid addition salt, the free base can beobtained by basifying a solution of the acid salt. Conversely, if theproduct is a free base, an addition salt, particularly apharmaceutically acceptable addition salt, may be produced by dissolvingthe free base in a suitable organic solvent and treating the solutionwith an acid, in accordance with conventional procedures for preparingacid addition salts from base compounds.

Non-toxic pharmaceutically acceptable salts include salts of acids suchas hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as, for example, acetic,HOOC—(CH₂)_(n)—COOH where n is 0-4, such as, for example, oxalic (n=0),and the like. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By the terms (C₁-C₆)alkyl and lower alkyl is meant straight and branchedchain alkyl groups having from 1-6 carbon atoms as well as cyclic alkylgroups such as, for example, cyclopropyl, cyclobutyl, or cyclohexyl.Specific examples of such alkyl groups are methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl andn-pentyl. Preferred C₁-C₆ alkyl groups are methyl, ethyl, propyl, butylor cyclopropylmethyl.

By the terms (C₁-C₆)alkoxy and lower alkoxy is meant straight andbranched chain alkoxy groups having from 1-6 carbon atoms.

By hydroxy C₁-C₆ alkyl is meant a C₁-C₆ alkyl group carrying a terminalhydroxy moiety.

By halogen, halo, or halide is meant fluorine, chlorine, bromine andiodine substituents.

The binding characteristics of compounds of Formula I for the D₄receptor, expressed in nM, generally range from about 0.5 nanomolar (nM)to about 50 nanomolar (nM). These compounds typically have bindingconstants for the D₂ receptor of from at least about 100 nM to more than3000 nM. Thus, the compounds of the invention are generally at leastabout 3, preferably at least about 5, and most preferably at least about10 time more selective for the D₄ receptor than the D₂ receptor. Evenmore preferably, these compounds are at least 20, and more preferably atleast 25-50, times more selective for the D₄ receptor than the D₂receptor.

As noted above, the invention also pertains to the use of compounds ofgeneral Formula I in the treatment of neuropsychological disorders.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. in addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe and partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preparation of 2-Aminoalkylaminoquinolines

The compounds of Formula I, and the pharmaceutically acceptable acidaddition salts thereof, may be prepared according to the reactions shownbelow in Schemes I and II.

wherein R₁-R₆, W, Y and Z are as defined above for Formula I.

As shown in Scheme I, a quinoline of general structure IV, possessing anappropriate leaving group (X) at the 2 position, e.g., a halogen orS-methyl group, may be reacted with a primary or secondary amine ofgeneral structure V in the presence of a base to afford a compound ofFormula I as the desired product. The reaction may be carried out atelevated temperature with or without a solvent. Further, the reactionmixture may also contain an acid scavenger such as diisopropylamine oran inorganic salt such as ammonium chloride.

Where they are not commercially available, the compounds of generalstructure IV may be prepared by literature procedures or proceduresanalogous to those described in the literature. Compounds of generalstructure V are either known or capable of being prepared by the methodsknown in the art. Those having skill in the art will recognize that thestarting materials may be varied and additional steps employed toproduce compounds encompassed by the present invention.

Alternatively, compounds of the invention may be prepared according tothe reactions shown in Scheme II. Thus, compounds may be prepared fromreadily available substituted or unsubstituted 4-haloquinoline compoundsby allowing them to react with a Wittig reagent, such as an alkyltriphenylphosphonate generated from an alkyltriphenylphosphonium halide,plus a base, such as n-butyllithium in an organic solvent, such astetrahydrofuran. The resulting 4-alkylquinoline can be converted to a4-alkyl-2-haloquinoline by treatment with an oxidizing agent, such asm-chloroperbenzoic acid (MCPBA) in an appropriate solvent, such aschloroform, to give the corresponding 4-alkylquinoline N-oxide, followedby reaction with a halogenating agent, such as phosphorus oxychloride togive a 4-alkyl-2-haloquinoline of Formula IVa. Reaction of2-haloquinoline IVa with amines of Formula V, as described above, yieldscompounds of this invention.

wherein R₁-R₆ are as defined above, R_(i) is alkyl of 1 to 4 carbonatoms, and X is halogen.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention. The invention is illustratedfurther by the following examples which are not to be construed aslimiting the invention in scope or spirit to the specific procedures andcompounds described in them.

EXAMPLE 1 Preparation of 1-(Pyrimidin-2-yl)-4-(2-aminoethyl)piperazine

A mixture of N-(2-bromoethyl)phthalimide (50.8 g, 0.2 mole),1-(pyrimidin-2-yl)piperazine (32.8 g, 0.2 mole) and potassium carbonate(55.2 g, 0.4 mole) in dimethyl formamide (400 mL) is heated at 80° C.for 16 hours under a nitrogen atmosphere. After cooling, the reactionmixture is poured into water (1 L) and ether (1 L). The heterogeneousmixture is then filtered to remove solids and the layers separated. Theaqueous layer is further extracted with ether (2×300 mL). The combinedorganic layers are dried (Na₂SO₄) and concentrated to provide colorlesscrystals (65 g, 96%, m.p. 132-133° C.).

A portion of the crystals (5 g, 15 mmol) is refluxed under nitrogen inhydrazine hydrate (50 mL) for 7 h. After cooling, the solution is pouredinto 30% potassium carbonate solution (50 mL) and extracted withmethylene chloride. The organic extracts are dried (Na₂SO₄) andconcentrated to give a pale yellow oil (3.27 g). This oil is dissolvedin methanol (5 mL) and combined with a methanolic solution (10 mL) offumaric acid (3.66 g). Isopropanol is then added (50 mL) and theresulting mixture concentrated on a hot plate to a volume of 20 mL. Uponcooling, the crystals of fumarate salt are collected (4.77 g, 99%, m.p.260° C. dec)

EXAMPLE 2 Preparation of(2-(4-pyrimidin-2-ylpiperazinyl)ethyl)-2-quinolylamine (Compound 1)

A solution of 1-(pyrimidin-2-yl)-4-(2-aminoethyl)piperazine (1 g) inxylene (200 mL) is treated with 2-chloroquinoline (1.5 g) and potassiumcarbonate (2 g). The mixture is then refluxed under N₂ overnight. Aftercooling, the solution is diluted with diethyl ether (200 mL) and washedwith water (3×50 mL). The organic layer is then extracted with anaqueous solution of 10% acetic acid. The aqueous extract is subsequentlywashed with ether (50 mL), basified with 50% NaOH solution and extractedwith ether. The ether layer is dried (K₂CO₃) and evaporated to give theproduct as an oil (0.47 g). The oil is dissolved in ethanol (20 mL),treated with 48% HBr until acidic and concentrated to a volume ofapprox. 5 mL. Upon cooling, the off-white crystalline hydrobromide saltis collected by filtration (0.45 g, mp 174-176° C.).

EXAMPLE 3 Preparation of2-3,4-dihydroquinolyl(2-(4-(2-pyridyl)piperazinyl)ethyl)amine (Compound2)

A solution of 3,4-dihydro-2(1H)-quinolinone (515 mg) andtrimethyloxonium tetrafluoroborate (590 mg) in 50 mL of dry pentenestabilized chloroform is stirred at room temperature overnight. To thismixture is then added 1-(pyridin-2-yl)-4-(2-aminoethyl)piperazine (800mg) and triethylamine (5 mL). The resultant solution is refluxedovernight under nitrogen. After cooling the solution is concentrated andpartitioned between water and ethyl acetate. The organic layer is driedand concentrated to give a brown oil. Purification using preparativethin layer chromatography on silica eluting with 10% CH₃OH, 89% CHCl₃,1% NH₄OH provides the product as a colorless oil (610 mg, R_(f)=0.51).This material is combined with 420 mg of fumaric acid in 5 mL ofmethanol. Isopropanol (20 mL) is added and the volume of solutionreduced to approximately 5 mL on a hot plate. Upon cooling, the product(700 mg, m.p. 200-202° C.) is collected by filtration.

EXAMPLE 4 Preparation of2-3,4-dihydroquinolyl(2-(4-(5-fluoropyrimidin-2-yl)piperazinyl)ethyl)amine(Compound 3)

A solution of 3,4-dihydro-2(1H)-quinolinone (515 mg) andtrimethyloxonium tetrafluoroborate (590 mg) in 50 mL of dry pentenestabilized chloroform is stirred at room temperature overnight. To thismixture is then added1-(5-fluoropyrimidin-2-yl)-4-(2-aminoethyl)piperazine (650 mg) andtriethylamine (5 mL). The resultant solution is refluxed overnight undernitrogen. After cooling the solution is concentrated and partitionedbetween water and ethyl acetate. The organic layer is dried andconcentrated. Purification using preparative thin layer chromatographyon silica eluting with 10% CH₃OH, 89% CHCl₃, 1% NH₄OH affords theproduct as a yellow oil (410 mg, R_(f)=0.46). This material is combinedwith 270 mg of fumaric acid in 5 mL of methanol. Isopropanol (20 mL) isadded and the solution reduced to a volume of approximately 5 mL on ahot plate. Upon cooling, the product (349 mg, m.p. 170-171° C.) iscollected by filtration.

EXAMPLE 5

The following compounds are prepared essentially according to theprocedures set forth above in Examples 1 and 2.

(a) (2-(4-pyrimidin-2-ylpiperazinyl)ethyl)-2-quinolylamine hydrobromide(Compound 4, m.p. 174-176° C.)

(b) (3-(4-pyrimidin-2-ylpiperazinyl)propyl)-2-quinolylamine hydrobromide(Compound 5, m.p. 127-128° C.)

(c) (4-(4-pyrimidin-2-ylpiperazinyl)butyl)-2-quinolylamine hydrobromide(Compound 6, m.p. 274-276° C.)

(d) (3-(4-(2-methoxyphenyl)piperazinyl)propyl)-2-quinolylamine fumarate(Compound 7, m.p. 159-160° C.)

(e) (3-(4-(2-pyridyl)piperazinyl)propyl)-2-quinolylamine hydrobromide(Compound 8, m.p. 137-139° C.)

(f) (3-(4-phenylpiperazinyl)propyl)-2-quinolylamine hydrobromide(Compound 9, m.p. 228-229° C.)

(g) (3-(4-(2,3-dimethylphenyl)piperazinyl)propyl)-2-quinolylaminefumarate (Compound 10, m.p. 186-187° C.)

(h) (4-methyl(2-quinolyl))(2-(4-pyrimidin-2-ylpiperazinyl)ethyl)aminehydrobromide (Compound 11, m.p. >270° C.)

(i) (4-methyl(2-quinolyl))(3-(4-pyrimidin-2-ylpiperazinyl)propyl)aminehydrobromide (Compound 12, m.p. 255-260° C.)

(j) (4-methyl(2-quinolyl))(4-(4-pyrimidin-2-ylpiperazinyl)butyl)aminehydrobromide (Compound 13, m.p. >260° C.)

(k)(4-methyl(2-quinolyl))(3-(4-(2-methoxyphenyl)piperazinyl)propyl)aminefumarate (Compound 14, m.p. 177-179° C.)

(l) (4-methyl(2-quinolyl))(3-(4-(2-pyridyl)piperazinyl)propyl)aminehydrobromide (Compound 15)

(m) (4-methyl(2-quinolyl))(3-(4-phenylpiperazinyl)propyl)amine fumarate(Compound 16, m.p. 208-209° C.)

(n)(4-methyl(2-quinolyl))(3-(4-(2,3-dimethylphenyl)piperazinyl)propyl)aminefumarate (Compound 17, m.p 159-160° C.)

(o) (2-(4-(5-fluoropyrimidin-2-yl)piperazinyl)ethyl)-2-quinolylaminehydrobromide (Compound 18, m.p. 150-151° C.)

(p)(4-methyl(2-quinolyl))(2-(4-(5-fluoropyrimidin-2-yl)piperazinyl)ethyl)aminehydrobromide (Compound 19, m.p. 250-253° C.)

(q) (4-(4-pyrimidin-2-ylpiperazinyl)butyl)-2-quinolylamine (compound 20)

(r) (3-(4-(2,3-dimethylphenyl)piperazinyl)propyl)-2-quinolylamine(Compound 21)

(s) (4-methyl(2-quinolyl))(3-(4-(pyrimidin-2-yl)piperazinyl)propyl)amine(Compound 22)

EXAMPLE 6

The following compounds are prepared essentially according to theprocedures set forth above in Examples 3 and 4.

(a) 2-3,4-dihydroquinolyl(2-(4-(pyrimidin-2-yl)piperazinyl)ethyl)aminefumarate (Compound 20, m.p. 217-218° C.)

(b) 2-3,4-dihydroquinolyl(3-(4-(pyrimidin-2-yl)piperazinyl)propyl)aminefumarate (Compound 21, m.p. 194-195° C.)

(c)2-3,4-dihydroquinolyl(4-(4-(5-fluoropyrimidin-2-yl)piperazinyl)butyl)aminehydrobromide (Compound 22, m.p. 279-280° C., dec)

(d)2-3,4-dihydroquinolyl(2-(4-(5-fluoropyrimidin-2-yl)piperazinyl)ethyl)aminefumarate (Compound 23, m.p. 200-201° C.)

(e)2-3,4-dihydroquinolyl(3-(4-(5-fluoropyrimidin-2-yl)piperazinyl)propyl)aminefumarate (Compound 24, m.p. 173-176° C.)

(f)2-3,4-dihydroquinolyl(4-(4-(5-fluoropyrimidin-2-yl)piperazinyl)butyl)aminefumarate (Compound 25, m.p. 182-183° C.)

(g)2-3,4-dihydroquinolyl(4-(4-(5-methylpyrimidin-2-yl)piperazinyl)butyl)aminefumarate (Compound 26, m.p. 253-254° C.)

(h) 2-3,4-dihydroquinolyl(2-(4-(2-pyridyl)piperazinyl)ethyl)aminefumarate (Compound 27)

(i) 2-3,4-dihydroquinolyl(3-(4-(2-pyridyl)piperazinyl)propyl)aminefumarate (Compound 28, m.p. 190-191° C.)

(j) 2-3,4-dihydroquinolyl(4-(4-(2-pyridyl)piperazinyl)butyl)aminefumarate (Compound 29, 154-155° C.)

(k) 1-(3-(2-3,4-dihydroquinolylamino)propyl)-4-phenylpiperidin-4-olhydrobromide (Compound 30, m.p. 247° C.)

(l)4-(4-chlorophenyl)-1-(3-(2-3,4-dihydroquinolylamino)propyl)piperidin-4-olhydrobromide (Compound 31, m.p. >260° C.)

EXAMPLE 7

The pharmaceutical utility of compounds of this invention is indicatedby the assays for dopamine receptor subtype affinity described below.

Representative examples of 2-aminoalkylaminoquinolines according to theinvention and representative corresponding biological acitvities areshown in Table 1 below. The number below each compound is its compoundnumber. Each of these compounds may be prepared according to thereactions described above and shown in Scheme I.

Compounds 1-4 in Table 1 have the following general formula A:

where R₃ and R₇ are defined in the table.

Compounds 5-6 in Table 1 have the following general formula B:

where R₃ and R₇ are defined in the table.

Assay for D₂ and D₄ Receptor Binding Activity

Pellets of COS cells containing recombinantly produced D₂ or D₄receptors from African Green monkey were used for the assays. The sampleis homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C.and pH 7.4. The sample is then centrifuged at 30,000×g and resuspendedand rehomogenized. The sample is then centrifuged as described and thefinal tissue sample is frozen until use. The tissue is resuspended 1:20(wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.4 ml of tissuesample, 0.5 nM ³H-YM 09151-2 and the compound of interest in a totalincubation of 1.0 ml. Nonspecific binding is defined as that bindingfound in the presence of 1 mM spiperone; without further additions,nonspecific binding is less than 20% of total binding. Bindingcharacteristics of various compounds of the invention for D₂ and D₄receptor subtypes are shown in Table 1.

Various compounds of the invention were also evaluated in M₁ and M₂Muscarinic subtype assays essentially as set forth in U.S. Pat. No.5,093,333. The acitivity of the compounds is shown in Table 1.

TABLE 1 Comound D₂ D₄ M₁ M₂ Number R₁ R₇ K_(i) (nM) K_(i) (nM) (nM) (nM)1 H

2720 10 264 299 11 CH₃

10 178 246 21 H

>100 22 22 CH₃

3300 10 2 H

>100 30 3 H

 8 128 144

Various compounds disclosed in U.S. Pat. No. 5,093,333 (Saab) wereevaluated in the D₄, M₁, and M₂ receptor assays as described above. Theactivity of these compounds is shown below in Table 2.

Saab Example No. Structure M₁ M₂ D₄ 1

1200 2500 >1000 2

2500 11600 >1000 3

600 2800 >1000 7

1300 20000 >1000

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or the pharmaceutically acceptable acid addition salts thereof wherein:R₁, R₂, R₃, R₄ and R₅ are the same or different and represent hydrogen,halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio, hydroxy, amino,mono(C₁-C₆) alkylamino, di(C₁-C₆) alkylamino, cyano, nitro,trifluoromethyl or trifluoromethoxy; R₆ is hydrogen or C₁-C₆ alkyl; W isCOH or CH; Y and Z independently represent nitrogen or CH; and Arepresents an alkylene group of from 2-5 carbon atoms optionallysubstituted with one or more alkyl groups having from one to four carbonatoms.
 2. A compound according to claim 1, wherein R₆ is hydrogen,methyl or ethyl.
 3. A compound according to claim 1, which is1-(3-(2,3,4-dihydroquinolylamino)propyl)-4-phenylpiperidin-4-olhydrobromide.
 4. A compound according to claim 1, which is4-(4-chlorophenyl)-1-(3-(2,3,4-dihydroquinolylamino)propyl)-4-phenylpiperidin-4-olhydrobromide.
 5. A compound according to claim 1, which is1-(3-(2,3,4-dihydroquinolylamino)propyl)-4-phenylpiperidin-4-ol.
 6. Acompound according to claim 1, which is4-(4-chlorophenyl)-1-(3-(2,3,4-dihydroquinolylamino)propyl)-4-phenylpiperidin-4-ol.7. A pharmaceutical composition comprising a compound according to claim1, together with at least one pharmaceutically acceptable carrier.
 8. Amethod for treatment of schizophrenia, psychotic depression, mania,Parkinson's disease and tardive diskinesia, which comprisesadministration to a patient in need thereof a therapeutically effectiveamount of a compound according to claim
 1. 9. A method for treatment ofmotion disorders related to the use of neuroleptic agents, comprisingadministration to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 1.